KR20160142383A - Novel crystal of tetracyclic compound - Google Patents
Novel crystal of tetracyclic compound Download PDFInfo
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Abstract
본 발명은 제약상 유용한 신규 결정인 9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴의 II형 및 III형 결정에 관한 것이다. The present invention relates to novel crystalline 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11-oxo-6,11-dihydro -5H-benzo [b] < / RTI > carbazole-3-carbonitrile.
Description
본 발명은 4환성 화합물 또는 그의 염 또는 수화물의 신규한 결정에 관한 것이다. The present invention relates to a novel crystal of a tetra-cyclic compound or a salt or hydrate thereof.
역형성 림프종 키나아제(Anaplastic Lymphoma Kinase;ALK)는 인슐린 수용체 패밀리에 속하는 수용체형 티로신키나아제 중 하나이다(비특허문헌 1, 비특허문헌 2). ALK의 유전자 이상은 다른 유전자와 융합된 이상 키나아제의 생성을 일으키는 것이 보고되어 있다. Anaplastic Lymphoma Kinase (ALK) is one of the receptor tyrosine kinases belonging to the insulin receptor family (Non-Patent
ALK의 이상을 수반하는 질환으로서, 예를 들면 암 및 암전이(비특허문헌 1, 특허문헌 1), 우울증, 인지기능장애(비특허문헌 2) 등이 알려져 있고, ALK 저해제의 제공은 그들 질환의 유효한 치료 및 예방제를 제공한다. Examples of the diseases accompanied by abnormality of ALK are cancer and cancer (
ALK 저해 작용을 갖는 화합물로서, 화학식 I으로 표시되는 화합물(화합물명:9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴) 등이 알려져 있다(특허문헌 3, 특허문헌 4, 특허문헌 5). (Compound: 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11 -Oxo-6,11-dihydro-5H-benzo [b] carbazole-3-carbonitrile) and the like are known (
[화학식 I](I)
그러나, 현재까지 화학식 I의 결정형태에 대해서는 보고되어 있지 않았다. However, the crystal form of the formula (I) has not been reported so far.
전술한 바와 같이 화학식 I으로 표시되는 화합물은 ALK 저해활성을 갖는 것이 알려져 있으나, 제약상 유용한 신규 결정이 요구되고 있었다. As described above, the compound represented by the general formula (I) is known to have an ALK inhibitory activity, but a new crystal useful in pharmaceuticals has been required.
본 발명자들은 예의 연구를 거듭한 결과, 화학식 I으로 표시되는 화합물의 신규 결정형(II형 결정, III형 결정)을 발견하였다.As a result of intensive studies, the present inventors have found a novel crystal form (II crystal, III crystal) of a compound represented by the formula (I).
즉, 본 발명의 한 측면에 의하면 아래의 (1)~(5)의 결정이 제공된다. That is, according to one aspect of the present invention, the following determinations (1) to (5) are provided.
(1) 분말 X선 회절 패턴에 있어서 9.2°±0.2°, 10.2°±0.2°, 16.2°±0.2°, 20.5°±0.2° 및 21.6°±0.2°의 회절각(2θ)에 피크를 갖는 화학식 I으로 표시되는 화합물의 일염산염의 결정. (1) A powder X-ray diffraction pattern having a peak at a diffraction angle (2?) Of 9.2 ± 0.2, 10.2 ± 0.2, 16.2 ± 0.2, 20.5 ± 0.2 and 21.6 ± 0.2, ≪ RTI ID = 0.0 > I < / RTI >
[화학식 I](I)
(2) 분말 X선 회절 패턴에 있어서 9.2°±0.2°, 10.2°±0.2°, 16.2°±0.2°, 17.5°±0.2°, 19.5°±0.2°, 20.5°±0.2°, 21.6°±0.2° 및 22.8°±0.2°의 회절각(2θ)에 피크를 갖는 (1)에 기재된 결정. (2) The powder X-ray diffraction pattern had a diffraction peak of 9.2, 0.2, 0.2, 16, 0.2, 17, 0.2, 20.5, And a peak at a diffraction angle (2 &thetas;) of 22.8 DEG +/- 0.2 DEG.
(3) 1 수화물 결정인, (1) 또는 (2)에 기재된 결정. (3) The crystal according to (1) or (2), which is a monohydrate crystal.
(4) 분말 X선 회절 패턴에 있어서 12.7°±0.2°, 14.3°±0.2°, 15.0°±0.2°, 18.5°±0.2°및 25.7°±0.2°의 회절각(2θ)에 피크를 갖는 화학식 I으로 표시되는 화합물의 일염산염의 결정. (4) A powder X-ray diffraction pattern having a peak at a diffraction angle (2?) Of 12.7 ° ± 0.2 °, 14.3 ° ± 0.2 °, 15.0 ° ± 0.2 °, 18.5 ° ± 0.2 ° and 25.7 ° ± 0.2 °, ≪ RTI ID = 0.0 > I < / RTI >
(5) 분말 X선 회절 패턴에 있어서 7.5°±0.2°, 12.7°±0.2°, 14.3°±0.2°, 15.0°±0.2°, 18.5°±0.2°, 20.3°±0.2°, 21.0°±0.2°및 25.7°±0.2°의 회절각(2θ)에 피크를 갖는, (4)에 기재된 결정. (5) The powder X-ray diffraction pattern was measured to be 7.5 占 0.2 占 12 占 占 0.2 占 14.3 占 0.2 占 15.0 占 0.2 占 18.5 占 0.2 占 20.3 占 0.2 占 21.0 占 0.2 And a peak at a diffraction angle (2 &thetas;) of 25.7 DEG +/- 0.2 DEG.
본 발명의 신규한 결정은 제약상 유용하다. The novel crystals of the present invention are useful in pharmaceuticals.
도 1은 II형 결정의 분말 X선 회절 측정결과의 그래프이다.
도 2는 III형 결정의 분말 X선 회절 측정결과의 그래프이다.
도 3은 I형 결정의 분말 X선 회절 측정결과의 그래프이다.
도 4는 II형 결정의 저습도 보관 후의 분말 X선 회절 측정결과의 그래프이다.
도 5는 상대습도 70%RH에서 보관 후의 II형 결정의 분말 X선 회절 측정결과의 그래프이다.
도 6은 상대습도 0%RH에서 90%RH까지 온도환경에 있어서의 II형 결정의 중량 변화율(%) 측정결과의 그래프이다. 1 is a graph of powder X-ray diffraction measurement results of II-form crystals.
Fig. 2 is a graph of the result of powder X-ray diffraction measurement of a III-form crystal.
Fig. 3 is a graph of powder X-ray diffraction measurement results of I-form crystals. Fig.
Fig. 4 is a graph showing the results of powder X-ray diffraction measurement of the II-form crystal after storage at low humidity.
5 is a graph of powder X-ray diffraction measurement results of II-form crystals after storage at a relative humidity of 70% RH.
FIG. 6 is a graph showing a measurement result of percent change in weight of II-type crystal in a temperature environment from 0% RH to 90% RH.
본 발명의 화학식 I의 화합물의 일염산염의 II형 결정은 후술하는 III형 결정을 약 40℃에서 감압 건조함으로써 취득할 수 있다.Form II crystals of the monohydrochloride of the compound of formula (I) of the present invention can be obtained by drying the III-form crystals described below at about 40 캜 under reduced pressure.
II형 결정은 분말 X선 회절 패턴에 있어서 9.2°, 10.2°, 16.2°, 20.5°및 21.6°의 회절각(2θ)에, 보다 구체적으로는 9.2°, 10.2°, 16.2°, 17.5°, 19.5°, 20.5°, 21.6°및 22.8°의 회절각(2θ)에 피크를 갖는 것을 특징으로 한다. II형 결정의 분말 X선 회절 측정결과의 일례를 도 1에 나타내고, 분말 X선 회절 패턴에 있어서의 피크의 일례를 표 1에 나타낸다. The II-form crystals exhibit diffraction angles (2 &thetas;) of 9.2 DEG, 10.2 DEG, 16.2 DEG, 20.5 DEG and 21.6 DEG in the powder X-ray diffraction pattern, more specifically 9.2 DEG, 10.2 DEG, 16.2 DEG, And has peaks at diffraction angles (2 &thetas;) of 20 DEG, 20.5 DEG, 21.6 DEG and 22.8 DEG. An example of the powder X-ray diffraction measurement results of the II-form crystal is shown in Fig. 1, and an example of the peaks in the powder X-ray diffraction pattern is shown in Table 1.
본 발명의 일 태양에 있어서 II형 결정은 1 수화물이다. 여기서 1 수화물이란, 의약품이 통상 보존·사용되는 환경하(온도, 상대습도 등)에서 안정하게 약 1 당량의 수분을 유지하는 결정이라면 특별히 한정되지 않는다.In one aspect of the present invention, the Form II crystal is a monohydrate. Here, the monohydrate is not particularly limited as long as it is a crystal which stably retains about one equivalent of the water under the environment where the medicine is normally stored and used (temperature, relative humidity, etc.).
본 발명의 화학식 I의 화합물의 일염산염의 III형 결정은 화학식 I의 화합물을 포함하는 용액을, 에탄올 및 염산의 혼합액(화학식 I의 화합물에 대해 1 당량 이상의 염산을 포함함)으로 혼합액 온도를 15℃ 부근으로 유지하면서 적하함으로써 취득할 수 있다.Form III crystals of the monohydrochloride salt of the compound of formula (I) of the present invention are prepared by dissolving a solution comprising the compound of formula (I) in a mixture of ethanol and hydrochloric acid (containing at least 1 equivalent of hydrochloric acid with respect to the compound of formula (I) Lt; RTI ID = 0.0 > C, < / RTI >
III형 결정은 분말 X선 회절 패턴에 있어서 12.7°, 14.3°, 15.0°, 18.5°및 25.7°의 회절각(2θ)에, 보다 구체적으로는 7.5°, 12.7°, 14.3°, 15.0°, 18.5°, 20.3°, 21.0°및 25.7°의 회절각(2θ)에 피크를 갖는 것을 특징으로 한다. III형 결정의 분말 X선 회절 측정결과의 일례를 도 2에 나타내고, 분말 X선 회절 패턴에 있어서의 피크의 일례를 표 2에 나타낸다.The III-form crystals have diffraction angles (2?) Of 12.7 °, 14.3 °, 15.0 °, 18.5 ° and 25.7 ° in the powder X-ray diffraction pattern, more specifically 7.5 °, 12.7 °, 14.3 °, 15.0 °, 18.5 , 20.3 DEG, 21.0 DEG and 25.7 DEG at a diffraction angle (2 &thetas;). An example of the result of the powder X-ray diffraction measurement of the III-form crystal is shown in Fig. 2, and an example of the peak in the powder X-ray diffraction pattern is shown in Table 2.
본 발명에 있어서 분말 X선 회절에 의한 분석은, 예를 들면 일본약국방(제15 개정)에 기재되어 있는 「분말 X선 회절 측정법」 등의 통상의 방법에 따라 행할 수 있다. 또한 일본약국방에 의하면 동일 결정형의 경우에는 일반적으로 회절각 2θ는 ±0.2도의 범위 내에서 일치한다고 설명되어 있다. 따라서, 분말 X선 회절에 있어서의 피크의 회절각이 완전히 일치하는 결정뿐 아니라, 피크의 회절각이 ±0.2도 정도의 오차로 일치하는 결정도 본 발명에 포함된다. In the present invention, analysis by powder X-ray diffraction can be carried out according to a conventional method such as " powder X-ray diffraction measurement method " described in Japanese Pharmacopoeia (15th ed.). Further, according to the Japanese Pharmacopoeia, in the case of the same crystal form, it is generally stated that the
분말 X선 회절 분석 측정 조건의 일례를 아래에 나타낸다:An example of a powder X-ray diffraction analysis measuring condition is shown below:
측정장치:X'Pert-Pro MPD(PANalytical 제조) Measuring apparatus: X'Pert-Pro MPD (manufactured by PANalytical)
대음극:Cu Large negative electrode: Cu
관전압:45 kV Tube voltage: 45 kV
관전류:40 mA Tube current: 40 mA
스텝 폭:0.02 Step width: 0.02
주사축:2θ Scanning axis: 2?
스텝당 샘플링 시간:43초 Sampling time per step: 43 seconds
주사범위:3~40° Scanning range: 3 to 40 °
결정의 수분량은 통상의 방법으로, 예를 들면 동적 수분 흡착 등온장치, 칼 피셔(Karl Fischer)법으로 측정할 수 있다. The water content of the crystal can be measured by a conventional method, for example, by a dynamic moisture adsorption isothermal apparatus or Karl Fischer method.
동적 수분 흡착 등온장치의 측정 조건의 일례를 아래에 나타낸다:An example of the measurement conditions of the dynamic moisture adsorption isotherm apparatus is shown below:
동적 수분 흡착 등온장치:DVS-1(Surface Mesurement Systems) Dynamic Moisture Adsorption Isotherms: DVS-1 (Surface Mesurement Systems)
온도:25℃ 부근의 일정 온도 Temperature: constant temperature around 25 ℃
분위기 가스:건조 질소 Atmosphere gas: dry nitrogen
분위기 가스의 유량:200 sccm(mL/min) Flow rate of atmosphere gas: 200 sccm (mL / min)
최소 대기시간:10 min Minimum wait time: 10 min
최대 대기시간:1,200 min
Maximum wait time: 1,200 min
칼 피셔 분석장치를 사용한 수분 측정법의 측정 조건의 일례를 아래에 나타낸다:An example of the measurement conditions of the moisture measurement method using the Karl Fischer analyzer is shown below:
분석법:전량 적정법, Analytical method:
KF 분석장치:미량 수분 측정장치 모델 KF-100(미츠비시 케미컬 제조) KF analysis apparatus: a micro-moisture measuring apparatus model KF-100 (manufactured by Mitsubishi Chemical)
양극액:아쿠아미크론 AX(미츠비시 케미컬 제조) Anion liquid: Aqua micron AX (manufactured by Mitsubishi Chemical)
음극액:아쿠아미크론 CXU(미츠비시 케미컬 제조). Cathode solution: Aqua micron CXU (manufactured by Mitsubishi Chemical).
본 발명자들은 추가로 II형 결정 및 III형 결정과 상이한 상기 화학식 I의 화합물의 결정(이하, I형 결정이라 칭함)을 특정하였다. I형 결정은 화학식 I의 화합물을 포함하는 용액을, 에탄올 및 염산의 혼합액(화학식 I의 화합물에 대해 1몰 당량 이상의 염산을 포함함)으로 혼합액 온도를 약 35℃ 이상으로 유지하면서 적하함으로써 취득할 수 있다. I형 결정은 분말 X선 회절 패턴에 있어서 8.4°, 14.0°, 16.7°, 18.8°, 23.3°의 회절각(2θ)에 피크를 갖는 것을 특징으로 한다. I형 결정의 분말 X선 회절 측정결과의 일례를 도 3에 나타내고, 분말 X선 회절 패턴에 있어서의 피크의 일례를 표 3에 나타낸다.The present inventors further specified crystals of the compound of formula (I) (hereinafter referred to as I-form crystal) different from the II-form crystals and the III-form crystals. The I-form crystal is obtained by dropping a solution containing the compound of formula (I) in a mixed solution of ethanol and hydrochloric acid (containing at least 1 molar equivalent of hydrochloric acid with respect to the compound of formula (I)) while maintaining the mixture temperature at about 35 캜 or higher . The I-form crystal is characterized by having peaks at diffraction angles (2 [theta]) of 8.4 DEG, 14.0 DEG, 16.7 DEG, 18.8 DEG and 23.3 DEG in the powder X-ray diffraction pattern. An example of the result of the powder X-ray diffraction measurement of the I-form crystal is shown in Fig. 3, and an example of the peak in the powder X-ray diffraction pattern is shown in Table 3.
화학식 I으로 표시되는 화합물 및 그의 염산염은 특허문헌 3~5에 기재된 방법에 따라 제조할 수 있으나, 이에 한정되는 것은 아니다. The compound represented by the formula (I) and the hydrochloride thereof can be produced according to the methods described in
실시예Example
아래에 본 발명의 바람직한 실시예에 대해서 더욱 상세하게 설명하나, 본 발명은 이들 실시예에 한정되는 것은 아니다. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, preferred embodiments of the present invention will be described in detail, but the present invention is not limited to these embodiments.
[실시예 1][Example 1]
9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴 일염산염의 I형 결정Synthesis of 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11-oxo-6,11-dihydro- -3-carbonitrile monohydrochloride
9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴 400 g을 메틸에틸케톤 4.8 L, 초산 1.44 L 및 증류수 1.68 L의 혼합용매에 실온에서 용해하고, 이 용액을 에탄올 12 L 및 2N 염산 0.8 L의 혼합물 중에 60℃에서 적하하였다. 석출된 고체를 여과하여 모아 에탄올 2 L로 세정 건조하여 표제 화합물의 일염산염의 I형 결정 357 g을 얻었다. Synthesis of 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11-oxo-6,11-dihydro- -3-carbonitrile was dissolved in a mixed solvent of 4.8 L of methyl ethyl ketone, 1.44 L of acetic acid and 1.68 L of distilled water at room temperature, and this solution was added dropwise at 60 DEG C in a mixture of 12 L of ethanol and 0.8 L of 2N hydrochloric acid. The precipitated solid was collected by filtration, washed with 2 L of ethanol and dried to obtain 357 g of the monohydrochloride of the title compound, I-form crystal.
[실시예 2][Example 2]
9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴 일염산염의 III형 결정Synthesis of 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11-oxo-6,11-dihydro- -3-carbonitrile < / RTI > < RTI ID =
9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴(9.00 g)을 메틸에틸케톤(90 ㎖), 증류수(31.5 ㎖) 및 초산(27.0 ㎖)의 혼합용매에 용해하였다. 이 용액을 15℃에서 교반한 에탄올(90 ㎖) 및 2N 염산(18.00 ㎖)의 혼합액으로 혼합액 온도를 15℃로 유지하면서 적하하였다. 계속해서 메틸에틸케톤(18.00 ㎖), 증류수(6.30 ㎖) 및 초산(5.40 ㎖)의 혼합용매로 충분히 세정한 후, 15℃에서 교반하였다. 석출된 고체를 여과하여 모아 표제 화합물의 일염산염의 III형 결정을 얻었다. Synthesis of 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11-oxo-6,11-dihydro- -3-carbonitrile (9.00 g) was dissolved in a mixed solvent of methyl ethyl ketone (90 ml), distilled water (31.5 ml) and acetic acid (27.0 ml). This solution was added dropwise to a mixture of ethanol (90 ml) and 2N hydrochloric acid (18.00 ml) which had been stirred at 15 ° C while maintaining the mixture temperature at 15 ° C. Subsequently, the mixture was sufficiently washed with a mixed solvent of methyl ethyl ketone (18.00 ml), distilled water (6.30 ml) and acetic acid (5.40 ml), and stirred at 15 ° C. The precipitated solid was collected by filtration to obtain Form III crystals of the monohydrochloride of the title compound.
[실시예 3][Example 3]
9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴 일염산염의 II형 결정Synthesis of 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11-oxo-6,11-dihydro- -3-carbonitrile < / RTI > < RTI ID =
실시예 2에서 얻어진 III형 결정을 에탄올(90 ㎖)로 세정한 후에 40℃에서 약 16시간 감압 건조하여 표제 화합물의 일염산염의 II형 결정을 얻었다. The III-form crystals obtained in Example 2 were washed with ethanol (90 ml) and dried under reduced pressure at 40 캜 for about 16 hours to obtain the II-form crystals of the monohydrochloride of the title compound.
[실시예 4][Example 4]
9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴 일염산염의 II형 결정Synthesis of 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11-oxo-6,11-dihydro- -3-carbonitrile < / RTI > < RTI ID =
9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴(4.00 g)을 메틸에틸케톤(40 ㎖), 증류수(14 ㎖) 및 초산(12 ㎖)의 혼합용매에 첨가하여 35℃에서 용해하였다. 이 용액을 에탄올(40 ㎖) 및 2N 염산(8.00 ㎖)의 혼합액(15℃에서 교반)으로 혼합액 온도를 15℃로 유지하면서 적하하였다. 이 혼합액에 추가로 메틸에틸케톤(8.00 ㎖), 증류수(2.80 ㎖) 및 초산(2.40 ㎖)의 혼합용매를 혼합액 온도를 15℃로 유지하면서 적하하였다. 계속해서 혼합액을 15℃에서 교반하였다. 석출된 고체를 여과하여 모아 에탄올(40 ㎖)로 세정한 후에 40℃에서 감압 건조하여 표제 화합물의 일염산염의 II형 결정(2.4805 g)을 얻었다. Synthesis of 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11-oxo-6,11-dihydro- -3-carbonitrile (4.00 g) was added to a mixed solvent of methyl ethyl ketone (40 ml), distilled water (14 ml) and acetic acid (12 ml) and dissolved at 35 캜. This solution was added dropwise to a mixed solution of ethanol (40 ml) and 2N hydrochloric acid (8.00 ml) (stirring at 15 캜) while maintaining the mixture temperature at 15 캜. A mixed solvent of methyl ethyl ketone (8.00 ml), distilled water (2.80 ml) and acetic acid (2.40 ml) was added dropwise to the mixed solution while the temperature of the mixture was maintained at 15 캜. Subsequently, the mixture was stirred at 15 占 폚. The precipitated solid was collected by filtration, washed with ethanol (40 ml) and dried under reduced pressure at 40 ° C to obtain II-form crystals of the monohydrochloride of the title compound (2.4805 g).
[실시예 5][Example 5]
9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴 일염산염의 III형 결정Synthesis of 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11-oxo-6,11-dihydro- -3-carbonitrile < / RTI > < RTI ID =
9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴(4.00 g)을 메틸에틸케톤(40 ㎖), 증류수(14 ㎖) 및 초산(12 ㎖)의 혼합용매에 첨가하여 35℃에서 용해하였다. 이 용액을 에탄올(40 ㎖) 및 2N 염산(8.00 ㎖)의 혼합액(15℃에서 교반)으로 혼합액 온도를 15℃로 유지하면서 적하하였다. 메틸에틸케톤(8.00 ㎖), 증류수(2.80 ㎖) 및 초산(2.40 ㎖)의 혼합용매를 혼합액 온도를 15℃로 유지하면서 적하하였다. 계속해서 혼합액을 15℃에서 교반하였다. 석출된 고체를 여과하여 모아 표제 화합물의 일염산염의 III형 결정(7.8435 g)을 얻었다. Synthesis of 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11-oxo-6,11-dihydro- -3-carbonitrile (4.00 g) was added to a mixed solvent of methyl ethyl ketone (40 ml), distilled water (14 ml) and acetic acid (12 ml) and dissolved at 35 캜. This solution was added dropwise to a mixed solution of ethanol (40 ml) and 2N hydrochloric acid (8.00 ml) (stirring at 15 캜) while maintaining the mixture temperature at 15 캜. A mixed solvent of methyl ethyl ketone (8.00 ml), distilled water (2.80 ml) and acetic acid (2.40 ml) was added dropwise while maintaining the temperature of the mixture at 15 ° C. Subsequently, the mixture was stirred at 15 占 폚. The precipitated solid was collected by filtration to obtain III-form crystals of monohydrochloride of the title compound (7.8435 g).
[시험예 1] 분말 X선 회절 분석[Test Example 1] Powder X-ray diffraction analysis
9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴 일염산염의 I형, II형, III형 결정에 대해서 분말 X선 회절을 아래의 조건으로 측정하였다. II형 결정, III형 결정, I형 결정의 측정결과를 도 1, 2, 3에 나타낸다.Synthesis of 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11-oxo-6,11-dihydro- -3-carbonitrile monohydrochloride, powder X-ray diffraction was measured under the following conditions. The measurement results of II-form crystals, III-form crystals and I-form crystals are shown in FIGS. 1, 2 and 3.
측정장치:X'Pert-Pro MPD(PANalytical 제조) Measuring apparatus: X'Pert-Pro MPD (manufactured by PANalytical)
대음극:Cu Large negative electrode: Cu
관전압:45 kV Tube voltage: 45 kV
관전류:40 mA Tube current: 40 mA
스텝 폭:0.02 Step width: 0.02
주사축:2θ Scanning axis: 2?
스텝당 샘플링 시간:43초 Sampling time per step: 43 seconds
주사범위:3~40° Scanning range: 3 to 40 °
[시험예 2] II형 결정의 습도에 따른 결정형 전이 확인[Test Example 2] Confirmation of crystal type transition according to humidity of type II crystal
9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴 일염산염의 II형 결정에 대해서 습도에 따른 결정형 전이 확인을 위해 아래의 습도 조건에 시료를 설치하고, 분말 X선 회절을 이용하여 결정형의 변화를 확인하였다. Synthesis of 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11-oxo-6,11-dihydro- -3-carbonitrile monohydrochloride, a sample was placed under the following humidity conditions to confirm the crystal type transition according to humidity, and the change of crystal form was confirmed by powder X-ray diffraction.
시험 조건 1(II형 결정의 저습도하에서의 결정형 전이 확인)Test condition 1 (Confirmation of crystal form transition of II-type crystal under low humidity)
시료량:약 17 ㎎ Sample amount: about 17 mg
온도:25℃ 부근의 일정 온도 Temperature: constant temperature around 25 ℃
분위기 가스:건조 질소 Atmosphere gas: dry nitrogen
분위기 가스의 유량:200 sccm(mL/min) Flow rate of atmosphere gas: 200 sccm (mL / min)
질량 변화율:0.002 dm/dt(%/min) Mass change rate: 0.002 dm / dt (% / min)
상대습도:0%RH의 상대습도하에 시료를 설치하였다. Relative humidity: The sample was installed under a relative humidity of 0% RH.
최소 대기시간:10 min Minimum wait time: 10 min
최대 대기시간:1,200 min Maximum wait time: 1,200 min
시험 조건 2(II형 결정의 고습도하에서의 결정형 전이 확인)Test condition 2 (Confirmation of crystal type transition under high humidity of II-form crystal)
시료량:약 16 ㎎ Sample amount: about 16 mg
온도:25℃ 부근의 일정 온도 Temperature: constant temperature around 25 ℃
분위기 가스:건조 질소 Atmosphere gas: dry nitrogen
분위기 가스의 유량:200 sccm(mL/min) Flow rate of atmosphere gas: 200 sccm (mL / min)
질량 변화율:0.002 dm/dt(%/min) Mass change rate: 0.002 dm / dt (% / min)
상대습도:70%RH의 상대습도하에 시료를 설치하였다. Relative Humidity: The sample was installed at a relative humidity of 70% RH.
최소 대기시간:10 min Minimum wait time: 10 min
최대 대기시간:1,200 min Maximum wait time: 1,200 min
분말 X선 회절의 결과에 의해 II형 결정을 저습도하에 보관하면 다른 결정형으로 전이되는 것이 명확해졌다(도 4). 공기 중에 방치하면 1시간 이내에 급속하게 원래의 II형 결정의 결정형으로 돌아갔다. 이 사실로부터, II형 결정은 저습도 환경(상대습도 15%RH 이하)에서는 탈수되어 무수화물이 될 가능성이 생각된다. 또한 II형 결정은 결정수를 갖는 것이 명확해졌다. As a result of the powder X-ray diffraction, it was clarified that the II-form crystal was transferred to another crystal form when stored under low humidity (Fig. 4). When left in the air, it quickly returned to the crystalline form of the original II-type crystal within 1 hour. From this fact, it is considered that the II-form crystal is dehydrated in a low humidity environment (relative humidity of 15% RH or less) to become an anhydride. It was also clear that the II-form crystal had a crystal number.
II형 결정을 70%RH에서 보관한 결과, II형 결정의 분말 X선 회절 패턴과는 상이한 분말 X선 회절 패턴(도 5)을 나타낸 것으로부터, II형 결정을 고습도하에 보관하면 다른 결정형으로 전이되는 것이 명확해졌다. 이 결정을 공기 중에 방치하고 경시적으로 분말 X선 회절을 측정한 결과, 4시간 후의 측정에서는 원래의 II형 결정으로 돌아갔다. 이 사실로부터, II형 결정은 고습도 환경(상대습도 65%RH 이상)에서는 흡습하여 결정수를 갖는 다른 결정형이 될 것으로 생각된다. When the II-form crystal was stored at 70% RH, the powder X-ray diffraction pattern (Fig. 5) was different from the powder X-ray diffraction pattern of the II-form crystal. . The crystal was allowed to stand in the air and the powder X-ray diffraction was measured with time. As a result, the crystal was returned to the original II-type crystal after 4 hours of measurement. From this fact, it is considered that the II-form crystal becomes a different crystal form having a crystal number by moisture absorption in a high humidity environment (relative humidity of 65% RH or more).
[시험예 3] II형 결정의 수분 흡착 등온선의 측정[Test Example 3] Measurement of moisture adsorption isotherm of II type crystal
9-에틸-6,6-디메틸-8-(4-모르폴린-4-일-피페리딘-1-일)-11-옥소-6,11-디히드로-5H-벤조[b]카르바졸-3-카르보니트릴 일염산염의 II형 결정(약 5 ㎎)에 대해서 동적 수분 흡착 등온장치:DVS-1(Surface Mesurement Systems)을 사용해서 수분 흡착 등온선을 아래 조건으로 측정하였다. Synthesis of 9-ethyl-6,6-dimethyl-8- (4-morpholin-4-yl-piperidin- 1 -yl) -11-oxo-6,11-dihydro- -3-carbonitrile monohydrochloride (about 5 mg) was measured under the following conditions using a dynamic moisture adsorption isothermal apparatus: DVS-1 (Surface Mesurement Systems).
시험 조건Exam conditions
온도:25℃ 부근의 일정 온도 Temperature: constant temperature around 25 ℃
분위기 가스:건조 질소 Atmosphere gas: dry nitrogen
분위기 가스의 유량:200 sccm(mL/min) Flow rate of atmosphere gas: 200 sccm (mL / min)
최소 대기시간:10 min Minimum wait time: 10 min
최대 대기시간:1,200 min Maximum wait time: 1,200 min
질량 변화율:0.002 dm/dt(%/min), 단, 5, 10, 15, 55, 60, 65%RH에서는 0.001 dm/dt(%/min) (0.001 dm / dt (% / min)) at 5, 10, 15, 55,
상대습도:0, 5, 10, 15, 20, 30, 40, 50, 55, 60, 65, 70, 80, 90, 80, 70, 65, 60, 55, 50, 40, 30, 20, 15, 10, 5, 0%RH의 순으로 상대습도를 변화시켰다. 이것을 1 사이클로 해서 3 사이클 행하였다. 측정결과를 도 6에 나타낸다. II형 결정의 중량 변화율(%)은 25℃ 부근에 있어서 상대습도 0%RH에서 90%RH까지 온도환경을 변화시켰을 때, 상대습도 0%RH~15%RH의 범위에서 3.7%, 상대습도 15%RH~55%RH의 범위에서 0.05%, 상대습도 55%RH~65%RH의 범위에서 11%, 상대습도 65%RH~90%RH의 범위에서 0.04%였다. Relative Humidity: 0,5,10,15,20,30,40,50,55,60,65,70,80,90,80,70,65,60,55,50,40,30,20,15 , 10, 5, and 0% RH. This was performed for one cycle and three cycles. The measurement results are shown in Fig. The weight change rate (%) of the II-type crystal was 3.7% in the relative humidity range of 0% RH to 15% RH and the relative humidity of 15% when the temperature environment was changed from 0% RH to 90% RH in the range of% RH to 55% RH, 0.04% in the range of RH of 55% RH to 65% RH and 11% and 65% RH to 90% RH.
II형 결정을 화학식 I의 화합물의 1 염산염 1 수화물로 가정하면 분자량은 537.0928이 된다. 분자량 및 질량 변화율(%)로부터 II형 결정은 1 염산염 1 수화물이고, 0%RH 분위기하에 보존하면 탈수되어 1 염산염으로 전이될 것으로 생각된다. 또한 II형 결정은 습도 65%RH 이상의 고습도 환경에서는 흡습하여 1 염산염 4 수화물로 전이될 것으로 생각된다. Assuming the Form II crystal is monohydrochloride monohydrate of the compound of Formula I, the molecular weight is 537.0928. From the rate of change in molecular weight and mass (%), the II-form crystal is monohydrochloride monohydrate, and when stored under 0% RH atmosphere, it is deemed to be dehydrated and converted into monohydrochloride. In addition, it is considered that the II-form crystal absorbs moisture in a high humidity environment of 65% RH or more and is converted into monohydrochloride tetrahydrate.
Claims (5)
[화학식 I]
(I) having peaks at diffraction angles (2?) Of 9.2 ° ± 0.2 °, 10.2 ° ± 0.2 °, 16.2 ° ± 0.2 °, 20.5 ° ± 0.2 ° and 21.6 ° ± 0.2 ° in the powder X- ≪ / RTI >
(I)
분말 X선 회절 패턴에 있어서 9.2°±0.2°, 10.2°±0.2°, 16.2°±0.2°, 17.5°±0.2°, 19.5°±0.2°, 20.5°±0.2°, 21.6°±0.2° 및 22.8°±0.2°의 회절각(2θ)에 피크를 갖는 결정. The method according to claim 1,
In the powder X-ray diffraction pattern, the values of 9.2 占 0.2 占 10.2 占 0.2 占 16.5 占 0.2 占 17.5 占 0.2 占 20.5 占 0.2 占 21.6 占 0.2 占 and 22.8 A crystal having a peak at a diffraction angle (2 &thetas;) of +/- 0.2 DEG.
1 수화물 결정인 결정. 3. The method according to claim 1 or 2,
1 Determination of the hydrate crystal.
분말 X선 회절 패턴에 있어서 7.5°±0.2°, 12.7°±0.2°, 14.3°±0.2°, 15.0°±0.2°, 18.5°±0.2°, 20.3°±0.2°, 21.0°±0.2° 및 25.7±0.2°의 회절각(2θ)에 피크를 갖는 결정. 5. The method of claim 4,
A powder X-ray diffraction pattern was observed at 7.5 ° ± 0.2 °, 12.7 ° ± 0.2 °, 14.3 ° ± 0.2 °, 15.0 ° ± 0.2 °, 18.5 ° ± 0.2 °, 20.3 ° ± 0.2 °, 21.0 ° ± 0.2 ° and 25.7 A crystal having a peak at a diffraction angle (2?) Of ± 0.2 °.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008280352A (en) | 2000-12-01 | 2008-11-20 | Kyowa Hakko Kirin Co Ltd | Composition improved in solubility and oral absorbability |
JP2009100783A (en) | 2006-10-11 | 2009-05-14 | Astellas Pharma Inc | Eml4-alk fusion gene |
JP4588121B1 (en) | 2009-06-10 | 2010-11-24 | 中外製薬株式会社 | Tetracyclic compounds |
JP4918630B1 (en) | 2010-08-20 | 2012-04-18 | 中外製薬株式会社 | Composition comprising a tetracyclic compound |
JP2012126711A (en) | 2010-11-22 | 2012-07-05 | Chugai Pharmaceut Co Ltd | Medicine containing four-ring compound |
Family Cites Families (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0892090A (en) | 1994-07-26 | 1996-04-09 | Tanabe Seiyaku Co Ltd | Medicinal composition |
DK0695755T3 (en) | 1994-08-04 | 1999-06-28 | Hoffmann La Roche | pyrrolocarbazoles |
AU703395B2 (en) | 1996-05-01 | 1999-03-25 | Eli Lilly And Company | Halo-substituted protein kinase C inhibitors |
EP1178988B1 (en) | 1999-05-14 | 2007-02-28 | The Australian National University | Compounds and therapeutic methods |
EP1603567A4 (en) | 2003-02-28 | 2006-10-18 | Inotek Pharmaceuticals Corp | Tetracyclic benzamide derivatives and methods of use thereof |
ES2263862T3 (en) | 2003-03-07 | 2006-12-16 | Istituto Nazionale Per Lo Studio E La Cura Dei Tumori | ANAPLASIC LYMPHOMA KINASE TEST, ITS REAGENTS AND COMPOSITIONS. |
GB0305929D0 (en) | 2003-03-14 | 2003-04-23 | Novartis Ag | Organic compounds |
CA2532800C (en) | 2003-07-23 | 2013-06-18 | Exelixis, Inc. | Anaplastic lymphoma kinase modulators and methods of use |
US7378414B2 (en) | 2003-08-25 | 2008-05-27 | Abbott Laboratories | Anti-infective agents |
WO2005054237A1 (en) | 2003-11-21 | 2005-06-16 | Novartis Ag | 1h-imidazoquinoline derivatives as protein kinase inhibitors |
AU2004296905A1 (en) | 2003-12-12 | 2005-06-23 | Merck Frosst Canada Ltd | Cathepsin cysteine protease inhibitors |
WO2005090304A1 (en) | 2004-03-19 | 2005-09-29 | Speedel Experimenta Ag | Organic compounds |
US7973061B2 (en) | 2004-03-31 | 2011-07-05 | Exelixis, Inc. | Anaplastic lymphoma kinase modulators and methods of use |
KR100859891B1 (en) | 2004-08-26 | 2008-09-23 | 화이자 인코포레이티드 | Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors |
GB0517329D0 (en) | 2005-08-25 | 2005-10-05 | Merck Sharp & Dohme | Stimulation of neurogenesis |
EP1945633A1 (en) | 2005-11-07 | 2008-07-23 | Irm Llc | Compounds and compositions as ppar modulators |
US7601716B2 (en) | 2006-05-01 | 2009-10-13 | Cephalon, Inc. | Pyridopyrazines and derivatives thereof as ALK and c-Met inhibitors |
US8063225B2 (en) | 2006-08-14 | 2011-11-22 | Chembridge Corporation | Tricyclic compound derivatives useful in the treatment of neoplastic diseases, inflammatory disorders and immunomodulatory disorders |
EP1914240B1 (en) | 2006-10-11 | 2009-12-02 | Astellas Pharma Inc. | EML4-ALK fusion gene |
WO2008051547A1 (en) | 2006-10-23 | 2008-05-02 | Cephalon, Inc. | Fused bicyclic derivatives of 2,4-diaminopyrimidine as alk and c-met inhibitors |
CN101687873A (en) | 2007-04-17 | 2010-03-31 | 百时美施贵宝公司 | 11 beta-hydroxysteroid dehydrogenase type i inhibitors with annelated heterocycles |
TWI389893B (en) | 2007-07-06 | 2013-03-21 | Astellas Pharma Inc | Di (arylamino) ary1 compound |
CN103923072B (en) | 2007-07-20 | 2017-05-31 | 内尔维阿诺医学科学有限公司 | As the substituted indazole derivative with kinase inhibitory activity |
JP5583592B2 (en) | 2007-11-30 | 2014-09-03 | ニューリンク ジェネティクス コーポレイション | IDO inhibitor |
AU2010244218B2 (en) | 2009-05-07 | 2012-07-19 | Astrazeneca Ab | Substituted 1-cyanoethylheterocyclylcarboxamide compounds 750 |
GB0910046D0 (en) | 2009-06-10 | 2009-07-22 | Glaxosmithkline Biolog Sa | Novel compositions |
US8609097B2 (en) | 2009-06-10 | 2013-12-17 | Hoffmann-La Roche Inc. | Use of an anti-Tau pS422 antibody for the treatment of brain diseases |
ES2692664T3 (en) | 2012-09-25 | 2018-12-04 | Chugai Seiyaku Kabushiki Kaisha | RET inhibitor |
JP2015185406A (en) | 2014-03-25 | 2015-10-22 | トヨタ自動車株式会社 | Fuel battery system, and method for controlling water content in fuel battery |
-
2015
- 2015-04-24 KR KR1020167031032A patent/KR20160142383A/en not_active Application Discontinuation
- 2015-04-24 US US15/126,045 patent/US9714229B2/en active Active
- 2015-04-24 JP JP2016515222A patent/JP6873698B2/en active Active
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- 2015-04-24 KR KR1020227009664A patent/KR20220042486A/en not_active Application Discontinuation
- 2015-04-24 RU RU2016146119A patent/RU2016146119A/en unknown
- 2015-04-24 MX MX2016013735A patent/MX2016013735A/en unknown
- 2015-04-24 CN CN202110843684.1A patent/CN113416179A/en active Pending
- 2015-04-24 CN CN201580020748.0A patent/CN106458967A/en active Pending
- 2015-04-24 EP EP15782464.0A patent/EP3135671B1/en active Active
- 2015-04-24 WO PCT/JP2015/062516 patent/WO2015163447A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008280352A (en) | 2000-12-01 | 2008-11-20 | Kyowa Hakko Kirin Co Ltd | Composition improved in solubility and oral absorbability |
JP2009100783A (en) | 2006-10-11 | 2009-05-14 | Astellas Pharma Inc | Eml4-alk fusion gene |
JP4588121B1 (en) | 2009-06-10 | 2010-11-24 | 中外製薬株式会社 | Tetracyclic compounds |
JP4918630B1 (en) | 2010-08-20 | 2012-04-18 | 中外製薬株式会社 | Composition comprising a tetracyclic compound |
JP2012126711A (en) | 2010-11-22 | 2012-07-05 | Chugai Pharmaceut Co Ltd | Medicine containing four-ring compound |
Non-Patent Citations (2)
Title |
---|
Nature, 제448권, 제561-566쪽, 2007년 |
Neuropsychopharmacology, 제33권, 제685-700쪽, 2008년 |
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